Animal Models of Ascending Genital-Tract Infection in Pregnancy

This article reviews animal models currently used for investigation of ascending genital-tract infection in pregnancy. The specific models reviewed are those in the rabbit, monkey, and mouse. These models investigate both the direct effects of bacteria in the setting of ascending infection and the role of cytokines produced by the immune system. For each model, experiments that delineate the pathophysiology of ascending genital-tract infection in pregnancy are described. Intervention experiments, including the use of antibiotics, anti-inflammatory agents, immunotherapy, and anti-cytokine therapy, are described. Comparison of these models is made with respect to pathogenesis in humans, reproducibility, anatomy, and cost

Randomized, Placebo-Controlled Trial of Transplacental Antibiotic Prophylaxis of Neonatal Group B Streptococcal Colonization and Bacteremia in Rabbits

Objective: We evaluated the effect of maternal administration of ampicillin/sulbactam on colonization and bacteremia in newborn rabbits after intracervical inoculation of mothers with group B streptococci (GBS)

Wall-liquid and wall-crystal interfacial free energies via thermodynamic integration: A molecular dynamics simulation study

A method is proposed to compute the interfacial free energy of a Lennard-Jones system in contact with a structured wall by molecular dynamics simulation. Both the bulk liquid and bulk face-centered-cubic crystal phase along the (111) orientation are considered. Our approach is based on a thermodynamic integration scheme where first the bulk Lennard-Jones system is reversibly transformed to a state where it interacts with a structureless flat wall. In a second step, the flat structureless wall is reversibly transformed into an atomistic wall with crystalline structure. The dependence of the interfacial free energy on various parameters such as the wall potential, the density and orientation of the wall is investigated. The conditions are indicated under which a Lennard-Jones crystal partially wets a flat wall.Comment: 15 pages, 11 figure

A Randomized Controlled Trial of Interleukin-1 Receptor Antagonist in a Rabbit Model of Ascending Infection in Pregnancy

Objective: To determinewhether treatment with interleukin-1 receptor antagonist (IL1-ra) would affect amniotic fluid concentrations of tumor necrosis factor alpha (TNF-α) and prostaglandins or clinical or microbiological outcomes in a model of ascending bacterial infection in pregnancy. Methods: Timed pregnant New Zealand white rabbits at 70% of gestation underwent endoscopic inoculation of the cervices with 10(6)–10(6) cfu Escherichia coli . Animals were randomly assigned in a blinded manner to a 5-h intravenous infusion of human IL1-ra (10 mg/kg) or placebo beginning 1 – 2 h after inoculation. Blood was drawn fromthe does for assay of serum IL1-ra concentration before inoculation, at mid-infusion, after the infusion ended and at necropsy. At necropsy, temperature and cultures were taken, and aspirated amniotic fluid was pooled for assays of TNF-α, prostaglandin E(2) (PGE(2)) and IL1-ra. Results: Serum IL1-ra concentrations rose to a mean of 2 mg/ml at mid-infusion and fell markedly after the infusion to concentrations barely detectable at necropsy. Between the two groups, there were no significant differences in the rates of fever or positive cultures or in amniotic fluid concentrations of PGE(2) or TNF-α.One unique finding was the demonstration that administration of human IL1-ra to the does resulted inmeasurable concentrationsof human IL1-ra in the amniotic fluid. Conclusions: Treatment with an intravenous infusion of human IL1-ra after cervical inoculation with E. coli did not affect clinical or microbiological outcomes or amniotic fluid concentrations of TNF-α or PGE(2). This experiment provides the first demonstration of passageof human IL1-ra from the maternal bloodstreamto the amniotic fluid

Development of a cost-effective optical sensor for continuous monitoring of turbidity and suspended particulate matter in marine environment

A cost-effective optical sensor for continuous in-situ monitoring of turbidity and suspended particulate matter concentration (SPM), with a production cost in raw materials less than 20 €, is presented for marine or fluvial applications. The sensor uses an infrared LED and three photodetectors with three different positions related to the light source-135º, 90º and 0º-resulting in three different types of light detection: backscattering, nephelometry and transmitted light, respectively. This design allows monitoring in any type of environment, offering a wide dynamic range and accuracy for low and high turbidity or SPM values. An ultraviolet emitter-receiver pair is also used to differentiate organic and inorganic matter through the differences in absorption at different wavelengths. The optical transducers are built in a watertight structure with a radial configuration where a printed circuit board with the electronic signal coupling is assembled. An in-lab calibration of the sensor was made to establish a relation between suspended particulate matter (SPM) or the turbidity (NTU) to the photodetectors' electrical output value in Volts. Two different sizes of seashore sand were used (180 µm and 350 µm) to evaluate the particle size susceptibility. The sensor was tested in a fluvial environment to evaluate SPM change during sediment transport caused by rain, and a real test of 22 days continuous in-situ monitoring was realized to evaluate its performance in a tidal area. The monitoring results were analysed, showing the SPM change during tidal cycles as well as the influence of the external light and biofouling problems.Funding Agency Programa Operacional Regional do Norte (NORTE2020), through Fundo Europeu de Desenvolvimento Regional (FEDER) NORTE-01-0145-FEDER-000032 European Union through the European Regional Development Fund, based on COMPETE 2020 (Programa Operacional da Competitividade e Internacionalizacao), project ICT UID/GEO/04683/2013 POCI-01-0145-FEDER-007690 Fundacao para a Ciencia e a Tecnologia (FCT)info:eu-repo/semantics/publishedVersio

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.

MotivationMultiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.ResultsWe performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementationDatasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary informationSupplementary data are available at Bioinformatics online

An immune clock of human pregnancy

The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies

Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset

Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 × 10−40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 × 10−7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies

Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome

Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy

Motivation Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia. Results We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified. Availability and implementation Datasets and scripts for reproduction of results are available through: Https://nalab.stanford.edu/multiomics-pregnancy/